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Vanilloids and endogenous cannabinoids mediate their actions via the vanilloid receptor subtype 1(VR1/TRPV1), a non-selective cation channel, which is widely distributed in the central and peripheral nervous system. Only recently, VR1 has been shown to be expressed in keratinocytes in vitro and in vivo. However, a precise description of VR1 localization in epithelial cells was missing. To determine this, we investigated VR1-immunoreactivity as well as mRNA and protein expression in a series of biopsies from normal, diseased, and capsaicin-treated human skin. VR1 was found in epidermal keratinocytes, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands upon immunohistochemistry, RT-PCR and Western blot analysis. Interestingly, in diseased skin such as prurigo nodularis, psoriasis vulgaris, and atopic dermatitis, VR1 expression in keratinocytes correlated with the degree of epidermal differentiation. Enhanced VR1 immunoreactivity and protein content was found in prurigo nodularis in which epidermal keratinocytes are highly differentiated. Under effective capsaicin therapy of prurigo nodularis, the epidermis thinned and the distribution pattern of VR1 on epidermal keratinocytes normalized. In psoriasis vulgaris, a disease with disturbed epidermal differentiation, less intense immunostaining for VR1 was observed. This could be confirmed by western blot analysis showing less VR1 protein amount in comparison to prurigo nodularis although histologically both showed a thickened epidermis. In atopic dermatitis, which is characterized by a moderate epidermal hyperplasia only and regular differentiated keratinocytes, VR1 immunoreactivity was unchanged in comparison to normal skin. These findings suggest that VR1 may contribute to regular differentiation of keratinocytes. VR1 activation opens non-selective cation channels with high permeability to calcium, a ion that is crucially important for the synthesis of cornification proteins such as involucrin, fillagrin and loricrin. The role of VR1 in other epithelial cells of appendage structures remains to be determined. In summary, VR1 is widely distributed in the skin suggesting a central role for this receptor not only in nociception but also maturation and function of epithelial cells. [ABSTRACT FROM AUTHOR]